The new context of the Psychology of Sustainability and Sustainable Development has reached the attention of the scientific community in recent years, due to its comprehensive approach aimed at enhancing the sustainability of interpersonal and intrapersonal talent, as well as of groups and communities. In this scenario, research on employee cross-cultural adjustment (CCA) is considered a key theme in human resource management. It is known that psychological support in the host country may alleviate distress and facilitate the integration of the expatriate workers. However, there is a lack of research investigating expatriate adjustment as an antecedent of the perceived organizational support. The aim of the study was to investigate the relationship among cross-cultural adjustment (CCA), perception of organizational support (POS), work-related stress (WRS), and innovation, considering these factors as a part of a unique innovative framework. A cross sectional study was performed using a sample of 234 expatriate workers of a multinational organization. Data were collected through a monitoring survey for the assessment of work-related stress risk factors of their expatriate staff. The results showed a positive correlation between CCA, POS, and innovation. On the other hand, a negative correlational effect of CCA and WRS, CCA and POS on WRS, and POS and WRS was found. Finally, POS was found to be a significant antecedent of CCA. These findings have implications for both international human resource management researchers and practitioners.